I am an Assistant Professor of Psychiatry at Boston University School of Medicine (BUSM) and a Clinical Research Psychologist in the National Center for Posttraumatic Stress Disorder (PTSD) at VA Boston Healthcare System. The proposed training plan of my K01 application, The Interplay of Genetic and Environmental Factors in the Comorbidity of PTSD and Disordered Eating, would greatly enhance my predoctoral training in psychology, behavioral genetics, and eating disorders. In order to accomplish my long- term goal of conducting genetically informed investigations of PTSD, eating and weight disorders, and related psychiatric comorbidity, I require training in advanced twin modeling methodology as well as molecular and genetic epidemiology research. A particular challenge of designing a 5-year training plan in psychiatric genetics is that the field changes quite rapidly. Thus, an overarching goal of this training plan, above and beyond learning specific techniques, is to build a solid foundation that will allow me to first keep up wih the moving target that is the field of psychiatric genetics and second to begin to design studies that will overcome some of the limitations of extant research. I propose a comprehensive training program in the etiology and psychobiology of PTSD, molecular genetics and genetic epidemiology, advanced twin modeling, network models of genetic and environmental factors, and epigenetics. This training will provide me with a strong knowledge base from which to generate hypotheses about psychiatric genetic mechanisms. For this career development award, I have carefully chosen a multidisciplinary mentorship team of top researchers in the fields of PTSD, eating disorders, and genetics. This mentorship, along with resources available at my institutions, will ensure that I have all the support necessary to meet my training and research goals. Both BUSM and VA Boston are committed to my career development and protected research time, as described in the attached letters. I will have unique access to facilities, resources, and collaborations at both outstanding institutions, including office space, libraries, and research equipment and technology. My overarching career goal is to apply the latest and best methods to the study of the genetic epidemiology of PTSD and disordered eating. This application will investigate the interplay of genetic and environmental factors in ther etiology and comorbidity. PTSD, a debilitating condition that affects 10.4% of women and 5% of men in the United States during their lifetimes, is highly comorbid with other medical and psychiatric diagnoses. In the National Comorbidity Survey-Replication study, 40% of women with lifetime BN and 26% of women with lifetime BED met criteria for lifetime PTSD, as did 66% of men with BN and 24% of men with BED. There are several psychosocial and genetic mechanisms that may account for PTSD - DE comorbidity. Trauma, which has been associated with bingeing and purging behaviors, may directly impact one's body image. In addition, PTSD and DE share common associated features, including alexithymia, emotion dysregulation, and impulsivity. DE behaviors also may serve as a means to self-medicate the symptoms of PTSD and associated negative affect. In addition, PTSD and DE likely share a common genetic vulnerability. However, there remains a need for investigation of genetic mechanisms of PTSD - DE comorbidity, as well as which of these mechanisms are common across disorders and those that are unique to the etiology of PTSD and DE. The proposed research will test three main models determine the nature of the comorbid relationship between PTSD and DE: 1) genetic vulnerability to PTSD and DE is triggered by trauma exposure, 2) PTSD and DE have common genetic and psychosocial vulnerabilities, and 3) prenatal maternal stress exposure leads to offspring epigenetic changes and DE. Three datasets will be used to address these three aims: 1) male participants in the Vietnam Era Twin Study of Aging (VETSA), 2) women from the Nurses Health Study II (NHS II), and 3) male and female offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC). Study 1 will test a series of twin models to investigate the extent to which the covariance of PTSD and DE is due to shared genetic and environmental influences and estimate the impact of gene-environment interaction. Study 2 will estimate a network model of genetic and psychosocial variables associated with PTSD and DE. Study 3 will investigate whether maternal prenatal stress exposure is associated with offspring genome-wide DNA methylation changes and DE. In addition, this study will investigate whether these associations apply to the etiology of substance use and depressive symptomatology, as well as DE. The proposed work is innovative in that it uses several cutting-edge methodologies to investigate the interplay of genetic and environmental factors in the etiology and comorbidity of PTSD and DE. It is expected that these disorders will share several key genetic and psychosocial vulnerabilities. Further, it is expected that exposure to prenatal stress will be associated with offspring adolescent DE and that this relation will be mediated by DNA methylation changes. Findings will provide a foundation for future genetic studies, as well as treatment and prevention efforts. Further, these outcomes are expected to position the Principal Investigator to submit a competitive R01 by the fourth year of the award period. PUBLIC HEALTH RELEVANCE: Posttraumatic stress disorder (PTSD) is highly comorbid with psychiatric and medical conditions; in particular, the alarming rates of overweight/obesity and disordered eating (DE) among individuals with PTSD underscore the public health significance of these conditions. The proposed research will be the first to examine genetic and environmental mechanisms of comorbidity between PTSD and DE, as well as gender differences in these associations. Findings from this innovative research will provide support for future genetic studies of psychiatric comorbidity and will inform treatment and prevention investigations among both women and men.